In Silico Inference of Synthetic Cytotoxic Interactions from Paclitaxel Responses.
Int J Mol Sci
; 22(3)2021 Jan 22.
Article
en En
| MEDLINE
| ID: mdl-33499282
ABSTRACT
To exploit negatively interacting pairs of cancer somatic mutations in chemotherapy responses or synthetic cytotoxicity (SC), we systematically determined mutational pairs that had significantly lower paclitaxel half maximal inhibitory concentration (IC50) values. We evaluated 407 cell lines with somatic mutation profiles and estimated their copy number and drug-inhibitory concentrations in Genomics of Drug Sensitivity in Cancer (GDSC) database. The SC effect of 142 mutated gene pairs on response to paclitaxel was successfully cross-validated using human cancer datasets for urogenital cancers available in The Cancer Genome Atlas (TCGA) database. We further analyzed the cumulative effect of increasing SC pair numbers on the TP53 tumor suppressor gene. Patients with TCGA bladder and urogenital cancer exhibited improved cancer survival rates as the number of disrupted SC partners (i.e., SYNE2, SON, and/or PRY) of TP53 increased. The prognostic effect of SC burden on response to paclitaxel treatment could be differentiated from response to other cytotoxic drugs. Thus, the concept of pairwise SC may aid the identification of novel therapeutic and prognostic targets.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Vejiga Urinaria
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Carcinoma
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Neoplasias Endometriales
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Paclitaxel
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Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Female
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Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2021
Tipo del documento:
Article